6- triazolyl 3-(trifluoromethyl)phenyl!methyl!-2-quinolines and -quinolinethiones

ABSTRACT

This invention is concerned with the compounds of formula ##STR1## the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, 
     wherein: R 1  is hydrogen, amino or C 1-4  alkyl; R 2  is hydrogen, halo or C 1-4  alkyl; R 3  is hydrogen, halo or C 1-4  alkyl; Y is 0 or S, and --X 1  ═X 2  --is a bivalent radical having the formula --N═CH--(a-1) or --CH═N--(a-2); 
     compositions containing the same, and processes of preparing these compounds. It further relates to their use as a medicine, in particular their use as a medicine to treat keratinization disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application is the national stage of application No. PCT/EP95/05173, filed on Dec. 21, 1995, which application claims priority fromEP 94.203.773.0, filed on Dec. 28, 1994.

The present invention concerns quinolinones and quinolinethiones,compositions containing the same, and processes of preparing thesecompounds. It further relates to their use as a medicine, in particular,their use as a medicine to treat keratinization disorders.

In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substitutedquinoline and quinolinone derivatives which suppress the plasmaelimination of retinoic acids. Some of these compounds also have theability to inhibit the formation of androgens from progestines and/orinhibit the action of the aromatase enzyme complex. A select group of(1H-triazol-1-ylmethyl) substituted quinolinone and quinolinethionesderivatives invariably being substituted with a3-(trifluoromethyl)phenyl moiety, is the subject of the presentinvention. The unexpected superiority of said select group of compoundsover the closest art-known compounds lies in their improved ability tosuppress keratinization effects.

Hence, the present invention is concerned with compounds of formula##STR2## the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein:

R¹ is hydrogen, amino or C₁₋₄ alkyl;

R² is hydrogen, halo or C₁₋₄ alkyl;

R³ is hydrogen, halo or C₁₋₄ alkyl;

Y is O or S; and

--X¹ ═X² --is a bivalent radical having the formula

--N═CH-- (a-1) or

--CH═N-- (a-2).

As used in the foregoing definitions the term halo is generic to fluoro,chloro, bromo and iodo. The term C₁₋₄ alkyl defines straight andbranched saturated hydrocarbons, having from 1 to 4 carbon atoms suchas, for example, methyl, ethyl, propyl, butyl, 1-methylethyl,1,1-dimethylethyl, 2-methylpropyl and the like.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the acid addition salt forms which canconveniently be obtained by treating the base form of the compounds offormula (I) with appropriate acids such as inorganic acids, for example,hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitricphosphoric and the like acids; or organic acids, such as, for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids. Conversely, said acidaddition salt forms can be converted in the free base forms by treatmentwith an appropriate base.

The term acid addition salt also comprises the hydrates and the solventaddition forms which the compounds of formula (I) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The term stereochemically isomeric forms as used herein defines all thepossible isomeric forms in which the compounds of formula (I) may occur.Unless otherwise mentioned or indicated, the chemical designation ofcompounds denotes the mixture of all possible stereochemically isomericforms, said mixtures containing all diastereomers and enantiomers of thebasic molecular structure. In particular, the compounds of formula (I)and some of the intermediates hereinafter have at least one stereogeniccenter in their structure. This stereogenic center may be present in a Rand a S configuration, said R and S notation is used in correspondancewith the rules described in Pure Appl. Chem., 1976, 45, 11-30.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.For instance, the compounds of formula (I) wherein R¹ is hydrogen mayexist in their tautomeric form.

Whenever used hereinafter, the term compounds of formula (I) is meant toinclude also the pharmaceutically acceptable acid addition salts and allstereoisomeric forms.

Particular compounds of the present invention are those compounds offormula (I) wherein --X¹ ═X² --is a bivalent radical of formula (a-1).

Other particular compounds are those compounds of formula (I) wherein R²is substituted on the 5 or 8 position of the quinolinone- orquinolinethione moiety.

Of special interest are those compounds wherein --X¹ ═X² --is a bivalentradical of formula (a-1) and Y is O.

Also of special interest are those compounds wherein Y is S and R² ishydrogen.

Further interesting compounds are those compounds of formula (I) whereinR¹, R² and R³ are hydrogen.

Another group of interesting compounds are those compounds of formula(I) for which the free base form has the R configuration.

Preferred compounds are those compounds of formula (I) wherein --X¹ ═X²--is a bivalent radical of formula (a-1), R¹ is hydrogen, amino ormethyl, R² is hydrogen and R³ is hydrogen, halo, methyl or ethyl.

More preferred compounds are those preferred compounds wherein Y is O,R¹ is hydrogen or methyl and R³ is hydrogen, methyl or ethyl.

Still more preferred compounds are: 6- 1H- 1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!methyl!-2(1H)-quinolinone, thepharmaceutically acceptable acid addition salts and the stereochemicallyisomeric forms thereof.

Most preferred is the compound (-)-(R)-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!-methyl!-2-(1H)-quinolinone and thepharmaceutically acceptable acid addition salts thereof.

The compounds of formula (I) wherein Y is O, said compounds beingrepresented by formula (I-b), can be prepared in accordance with theprocedures described in EP-0,371,564.

The compounds of formula (I-b) may further be converted into compoundsof formula (I) wherein Y is S, said compounds being represented byformula (I-c), using art-known transformation reagents such as, forexample, phosphorous pentasulfide. ##STR3##

Said compounds of formula (I-c) may be prepared by mixing the reagentsin a reaction-inert solvent such as, for example, pyridine. The reactionmay suitably be carried out at the reflux temperature of the reactionmixture.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, trituration and chromatography.

The compounds of formula (I-b) wherein R¹ is hydrogen, said compoundsbeing represented by formula (I-b-1), can be prepared by reacting anitrone of formula (II) with a suitable ester forming reagent such as,for example, the anhydride of a carboxylic acid, for instance, aceticanhydride, thus forming the corresponding ester on the 2 position of thequinoline moiety. Said quinoline ester can be hydrolyzed in situ to thecorresponding quinolinone using a base such as, for example, potassiumcarbonate. Stirring and elevated temperatures may enhance the rate ofthe reaction. ##STR4##

Alternatively, compounds of formula (I-b-1) can be prepared by reactinga nitrone of formula (II) with a sulfonyl containing electrophilicreagent such as, for example, p-toluenesulfonylchloride in the presenceof a base such as, for example, aqueous potassium carbonate. Thereaction initially involves the formation of a 2-hydroxyquinolinederivative which is subsequently tautomerized to the desired quinolinonederivative. Said reaction may suitably be conducted at room temperaturein a reaction-inert solvent such as, for example, dichloromethane ortoluene. Stirring and the application of art-known conditions of phasetransfer catalysis may enhance the rate of the reaction.

Compounds of formula (I-b-1) may also be prepared by an intramolecularphotochemical rearrangement of compounds of formula (II). Saidrearrangement can be carried out by dissolving the reagents in areaction-inert solvent and irradiating at a wavelength of, for instance,366 nm. It is advantageous to use degassed solutions and to conduct thereaction under an inert atmosphere such as, for example, oxygen freeargon or nitrogen gas, in order to minimize undesired side reactions orreduction of quantum yield. ##STR5##

Compounds of formula (I-b-1) may also be converted into compounds offormula (I-b) wherein R¹ is C₁₋₄ alkyl, said compounds being representedby formula (I-b-2). For example, compounds of formula (I-b-1) may beN-alkylated with C₁₋₄ alkyl-L wherein L is a reactive leaving group suchas for example, halo or a sulfonyloxy group, in the presence of a basesuch as, for example, sodium hydride. ##STR6##

Said N-alkylation may conveniently be carried out by mixing the reagentsin a reaction-inert solvent such as, for example, N,N-dimethylformamide.It may be advantageous to conduct said N-alkylation under an inertatmosphere such as, for example, argon or nitrogen gas.

The compounds of formula (I-b-1) may also be converted into compounds offormula (I-b) wherein R¹ is amino, said compounds being represented byformula (I-b-3). For example, compounds of formula (I-b-3) can beprepared by N-aminating compounds of formula (I-b-1) with an aminationagent such as, for example, hydroxylamine-O-sulfonic acid at roomtemperature in a solvent such as, for example, water and in the presenceof a base such as, for example, sodium hydroxide. ##STR7##

Nitrones of formula (II) may be prepared by N-oxidizing quinolines offormula (III) with an appropriate oxidizing agent such as, for example,m-chloro-peroxybenzoic acid or phtalic anhydride in combination withhydrogen peroxide. Said N-oxidation may be carried out by mixing thereagents at room temperature in a reaction-inert solvent such as, forexample, dichloromethane. Subsequent to the preparation of theintermediates of formula (II), the compounds of formula (I-b) mayconveniently be prepared by way of an in situ reaction. ##STR8##

Intermediates of formula (III) can be prepared following the proceduresdescribed in EP-0,371,564.

A novel approach to prepare the compounds of formula (I-b-1) wherein R³is hydrogen, said compounds being represented by formula (I-b-1-a),involves the procedure disclosed in scheme 1. The first step involvesthe protection of a quinolinone of formula (IV-1) wherein halorepresents a halogen atom, in particular, a bromine atom, thus forming aquinoline derivative of formula (IV-2) wherein Z is a protecting groupsuch as, for example, methyl. Said quinoline derivative is reacted withan organolithium compound such as, for example, n-buthyllithium, in areaction-inert solvent such as, for example, tetrahydrofuran, thussubstituting the halogen atom in the 6 position of the quinoline moietyin intermediates of formula (IV-2) with a lithium atom. Said lithiatedquinoline intermediate is reacted in situ with 3-trifluorobenzaldehydeor a functional derivative thereof, thus forming an intermediate offormula (IV-3). The formation of intermediates of formula (IV-3) fromintermediates of formula (IV-2) may conveniently be carried at lowtemperatures, preferably at -78° C. Intermediates of formula (IV-3) maybe oxidized to the corresponding ketones of formula (IV-4) usingart-known oxidizing agents. Said ketones may subsequently bedeprotected, thus forming the tautomeric quinolinone derivative offormula (IV-5) in the presence of an acid. Elevated temperatures andstirring may enhance the rate of the transformation reaction. ##STR9##

Compounds of formula (I-b-1-a) may be prepared by reductive alkylationof 1,2,4-triazole or 1,3,4-triazole with the compounds of formula(IV-5). Said reaction can conveniently be conducted by stirring andheating the reagents in the presence of formic acid or formamides asreducing agents optionally in the presence of an acid catalyst such as,for example, hydrochloric acid. If desired, the compounds of formula(I-b-1-a) may be further reacted according to the processes describedhereinabove for the compounds of formula (I-b) and (I-c).

The compounds of formula (I) and its intermediate compounds as preparedin the hereinabove described processes are generally racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. The racemic compounds of formula (I) or itsintermediate compounds may be converted into the correspondingdiastereomeric salt forms by reaction with a suitable chiral acid suchas, for example, camphorsulfonic acid. Said diastereomeric salt formsare subsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali.An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) or its intermediate compounds involves liquidchromatography using a chiral stationary phase. Said purestereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. For example, enantiomerically pure forms of thecompounds of formula (I) may be prepared from enantiomerically pureforms of compounds of formula (III). The enantiomerically pure compoundsof formula (III) may be prepared using art-known separation techniques.

The compounds of the present invention have superior pharmacologicalproperties compared to those of the closest art-compounds in that theyare more effective in suppressing keratinization effects which may bedemonstrated in the "Vaginal Keratinization Test on Ovariectomized Rats"as is described hereinafter. In view of their ability to suppresskeratinization effects, the compounds of formula (I) are useful in thetreatment and/or prevention of keratinization disorders such as, forexample, acne, psoriasis, severe psoriasis, lamellar ichthyosis, plantarwarts, callosities, acanthosis nigricans, lichen planus, molluscum,melasma, corneal epithelial abrasion, geographic tongue, Fox-Fordycedisease, cutaneous metastatic melanoma and keloids, epidermolytichyperkeratosis, Darier's disease, pityriasis rubra pilaris, congenitalichthyosiform erythroderma, hyperkeratosis palmaris et plantaris, andsimilar disorders.

The compounds of formula (I) also suppress the plasma elimination ofretinoids, such as all-trans-retinoic acid, 13-cis retinoic acid andtheir derivatives resulting in more sustained tissue concentrations ofretinoic acid and improved control of the differentiation and growth ofvarious cell types. The property to delay the metabolism of retinoicacid can be evidenced in various in vitro and in vivo experiments. Aparticular in vitro procedure is described hereinafter and tests theinhibitory activity of the compounds of formula (I) on the metabolism ofretinoic acid in human breast cancer cells. In view of their capabilityto delay the metabolism of retinoic acid, the present compounds areuseful in the prevention and/or the treatment of disorders characterizedby abnormal cell proliferation and/or differentiation, such as cancer,and, in particular, keratinization disorders such as those mentionedhereinabove (Van Wauwe et al. J. Pharmacol. Exp. Ther., 1992, 261(2),773-779).

Further, the compounds of formula (I) are useful in suppressing themetabolism of exogenously administered and of endogenously formed1α,25-dihydroxy-vitamin D₃ (calcitriol). The inhibitory activity of thecompounds of formula (I) on the metabolic degradation of calcitriol maybe evidenced by measuring the impact of said compounds on the calcitrioldegradation in human foreskin keratinocytes, pig kidney cells and humanhepatoma cells. In view of their inhibitory effect on the calcitriolmetabolism, the compounds of formula (I) can be used in the treatment ofvitamin D deficiency states. The "classic" application of vitamin Dcompounds lies in the field of metabolic bone disorders. Calcitriol hasalso been described to influence the effects and/or production ofinterleukins. Further, calcitriol is of use in the treatment of diseasescharacterized by abnormal cell proliferation and/or differentiation, inparticular, keratinization disorders such as those described hereinabove(Bouillon et al., Endocrine Reviews, 1995, 16, 200-257).

In addition, the compounds of formula (I) inhibit the formation ofandrogens from progestines and inhibit the action of the aromataseenzyme complex which catalyses the formation of estrogens fromandrogenic steroids in mammals.

In view of the above described uses of the compounds of formula (I), itfollows that the present invention provides a method of treatingwarm-blooded animals suffering from diseases which are characterized byan increased proliferation and/or abnormal differentiation of normal,preneoplastic or neoplastic cells, whether they are epithelial ormesenchymal; whether they are of ectodermal, endodermal or mesodermalorigin; or whether they are estrogen dependent, ancrogen dependent ornon-estrogen and non-androgen dependent. Said method comprises thesystemic or topical administration of a therapeutic amount of a compoundof formula (I) effective in treating the above described disorders, inparticular keratinization disorders, optionally in the presence of aneffective amount of a retinoic acid, a derivative or a stereochemicallyisomeric form thereof. The present invention further concerns a methodof treating patients suffering from a pathological condition which maybe beneficially influenced by the administration of calcitriol or aprodrug thereof, in particular keratinization disorders, said methodconsisting of administering to a patient (a) an effective amount ofcalcitriol or a prodrug thereof and (b) an effective amount of acompound of formula (I).

Thus, the present invention also relates to compounds of formula (I) asdefined hereinabove for use as a medicine, in particular, for use as amedicine to treat keratinization disorders. The present inventionfurther relates to compounds of formula (I) as defined hereinabove incombination with a retinoic acid, a derivative or a stereochemicallyisomeric form thereof, or in combination with calcitriol or a prodrugthereof, for use as a medicine. The present invention also relates tothe use of the compounds of formula (I) in the manufacture of amedicament for the treatment of the above described disorders, inparticular, keratinization disorders.

For ease of administration, the subject compounds may be formulated intovarious pharmaceutical forms. As appropriate compositions there may becited all compositions usually employed for systemically or topicallyadministering drugs. To prepare the pharmaceutical compositions of thisinvention, a therapeutically effective amount of the particularcompound, optionally in acid addition salt form, as the activeingredient is combined in intimate admixture with a pharmaceuticallyacceptable carrier, which may take a wide variety of forms depending onthe form of preparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. In the compositions suitable for percutaneous administration,the carrier optionally comprises a penetration enhancing agent and/or asuitable wettable agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g. as a transdermal patch, as a spot-onor as an ointment. Acid addition salts of compounds of formula (I) dueto their increased water solubility over the corresponding base form,are obviously more suitable in the preparation of aqueous compositions.As appropriate compositions for topical application there may be citedall compositions usually employed for topically administering drugs e.g.creams, gellies, dressings, shampoos, tinctures, pastes, ointments,salves, powders and the like. Application of said compositions may be byaerosol, e.g. with a propellent such as nitrogen, carbon dioxide, afreon, or without a propellent such as a pump spray, drops, lotions, ora semisolid such as a thickened composition which can be applied by aswab. In particular compositions, semisolid compositions such as salves,creams, gellies, ointments and the like will conveniently be used.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (included scoredor coated tablets), capsules, pills, powder packets, wafers, injectablesolutions or suspensions, teaspoonfuls, tablespoonfuls and the like, andsegregated multiples thereof.

Other such compositons are preparations of the cosmetic type, such astoilet waters, packs, lotions, skin milks or milky lotions. Saidpreparations contain, besides the active ingredient, components usuallyemployed in such preparations. Examples of such components are oils,fats, waxes, surfactants, humectants, thickening agents, antioxidants,viscosity stabilizers, chelating agents, buffers, preservatives,perfumes, dyestuffs, lower alkanols, and the like. If desired, furtheringredients may be incorporated in the compositions, e.g.antiinflamatory agents, antibacterials, antifungals, disinfectants,vitamins, sunscreens, antibiotics, or other anti-acne agents.

In a further aspect of the invention there are provided particularpharmaceutical or cosmetical compositions which comprise an inertcarrier, an effective amount of a compound of formula (I) and aneffective amount of a retinoic acid, a derivative thereof or astereochemically isomeric form thereof. Said retinoic acid containingcompositions are particularly useful for treating acne or for retardingthe effects of aging of the skin and generally improve the quality ofthe skin, particularly human facial skin.

Further, the invention also relates to particular pharmaceutical orcosmetical compositions which comprise an inert carrier, an effectiveamount of a compound of formula (I) and an effective amount ofcalcitriol or a prodrug thereof. The latter compositions areparticularly useful in treating keratinization disorders.

A particular embodiment of the invention relates to a product containingretinoic acid or a derivative thereof and a compound of formula (I) as acombined preparation for simultaneous, separate or sequential use indermatological disorders. The invention also relates to a productcontaining calcitriol or a prodrug thereof and a compound of formula (I)as a combined preparation for simultaneous, separate or sequential usein disorders beneficially affected by calcitriol. Such products maycomprise, for example, a kit comprising a container with a suitablecomposition containing a compound of formula (I) and another containerwith a composition containing calcitriol or a retinoid Such a productmay have the advantage that a physician can select on the basis of thediagnosis of the patient to be treated the appropriate amounts of eachcomponent and the sequence and timing of the administration thereof.

Those of skill in the treatment of keratinization disorders coulddetermine the effective therapeutic daily amount from the test resultspresented hereinafter. An effective therapeutic daily amount would befrom about 0.1 mg/kg to about 40 mg/kg body weight, more preferably fromabout 0. 3 mg/kg to about 10 mg/kg body weight. It may be appropriate toadminister the therapeutically effective dose once daily or as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.1 mg to 500 mg, and in particular, 0.5 mg to 50 mg ofactive ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the patient may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated patient and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned hereinabove are therefore only guidelines.

The following examples are intended to illustrate and not to limit thescope of the present invention.

EXPERIMENTAL PART A. Preparation of the Intermediates EXAMPLE 1

a) A mixture of ethyl 4-amino-2-chlorobenzoate (20 g), glycerol (32.17g) and sodium 3-nitrobenzenesulfonate (46.73 g) in sulfuric acid (75%)(160 ml) was stirred for 3 hours at 100° C. and for 1 hour at 140° C.After the mixture was cooled to 60° C. and ethanol (200 ml) was added,the mixture was stirred for 16 hours at 60° C. Ethanol was evaporatedand the residue was poured into ice water, neutralized with NH₄ OH andextracted with ethylacetate. The separated organic layer was dried overMgSO₄, filtered and the filtrate evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ /ethylacetate97.5/2.5). The desired pure fractions were collected and evaporated,yielding 7.56 g (28%) ethyl 5-chloro-6-quinolinecarboxylate(intermediate 1).

b) Lithiumaluminiumhydride (1.66 g) was added portionwise to a solutionof intermediate 1 (10.11 g) in tetrahydrofuran (325 ml) at 0° C. underN₂ and the mixture was stirred for 1 hour. Ethylacetate (70 ml) andwater (3 ml) were added to the mixture which was subsequently filtered.The filtrate was dried over MgSO₄, filtered and evaporated, yielding 7.9g (93%) 5-chloro-6-quinolinemethanol (intermediate 2).

c) A mixture of intermediate 2 (7.9 g) and manganese dioxide (10.64 g)in CH₂ Cl₂ (165 ml) was stirred for 6 hours at room temperature. Themixture was filtered over celite and the filtrate was stirred again withmanganese dioxide (10.64 g) for 24 hours. The mixture was filtered overcelite and the filtrate evaporated, yielding 7.82 g (100%)5-chloro-6-quinolinecaeboxaldehyde (intermediate 3). In a similarmanner, 8-fluoro-6-quinolinecarboxaldehyde (intermediate 4) wasprepared.

EXAMPLE 2

a) A solution of 1-bromo-3-(trifluoromethyl)benzene (10.67 g) intetrahydrofuran (15 ml) was added dropwise to a suspension of magnesiumturnings (1.15 g) in tetrahydrofuran (15 ml). The mixture was cooled to0° C. and a solution of intermediate 3 (7.57 g) in tetrahydrofuran (90ml) was added dropwise. The mixture was partitioned between ethylacetateand a saturated aqueous NH₄ Cl solution. The organic layer wasseparated, dried over MgSO₄, filtered and the filtrate evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂ Cl₂ /CH₃ OH 98/2). The pure fractions were collected and evaporated,yielding 10.9 g (81%) (±)-5-chloro-α-3-(trifluoromethyl)phenyl!-6-quinolinemethanol (intermediate 5).

b) Thionyl chloride (8 ml) was added dropwise to a solution ofintermediate 5 (8 g) in CH₂ Cl₂ (400 ml) at 0° C. and the mixture wasstirred at room temperature overnight. The solvent was evaporated andthe residue was partitioned between CH₂ Cl₂ and water which wasalkalized with a saturated K₂ CO₃ solution. The separated organic layerwas dried over MgSO4, filtered and the filtrate evaporated, yielding 8.4g (100%) (±)-5-chloro-6- chloro 3-(trifluoromethyl)phenyl!methyl!quinoline (intermediate 6).

c) A mixture of intermediate 6 (8.4 g), 1,2,4-triazole (4.89 g) andpotassium carbonate (9.78 g) in acetonitrile (300 ml) was stirred andrefluxed for 12 hours. The solvent was evaporated and the residue waspartitioned between CH₂ Cl₂ and water. The separated organic layer wasdried over MgSO₄, filtered and the filtrate evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH/NH₄ OH 98.5/1.5/0.1). The pure fractions were collected and thesolvent evaporated. The residue was crystallized from diisopropylether/petrol ether, yielding 1.51 g (32%) (±)-5-chloro-6-1H-1,2,4-triazol-1-yl 3-(trifluoromethyl)phenyl!-methyl!quinoline(intermediate 7; mp. 144.5° C.). In a similar manner, there wereprepared: (±)-8-methyl-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!methyl!quinoline (intermediate 8; mp. 108.9°C.) and (±)-8-fluoro-6- 1H-1,2,4-triazol-1-yl 3-(trifluoromethyl)phenyl!methyl!quinoline (intermediate 9; mp. 146.6° C.).

EXAMPLE 3

The racemic mixture of 6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!methyl!-quinoline (10 g), disclosed andexemplified in EP-371,564 was separated into its pure enantiomers on aChiracell OD® column (eluent: ethanol/hexanes 1/1). The pure fractionsof the first eluted peak were collected, combined and the solventevaporated, yielding 3.6 g (+)-(S)-6- 1H-1,2,4-triazol- 1-yl3-(trifluoromethyl)phenyl!methyl!-quinoline (intermediate 10). The purefractions of the second eluted peak were collected, combined andpartitioned with diethyl ether. The separated organic layer was filteredand the solvent evaporated, yielding 3.48 g (-)-(R)-6-1H-1,2,4-triazol-1-yl 3-(trifluoromethyl)phenyl!methyl!-quinoline(intermediate 11).

EXAMPLE 4

Iodomethane (8.8 ml) was added to a stirring mixture of (±)-6-1H-1,2,4-triazol-1-yl 3-(trifluoromethyl)phenyl!methyl!quinoline (10 g)in N,N-dimethylformamide (100 ml) at 0° C. under N₂. Potassiumt-butoxide (9.5 g) was added portionwise and the mixture was stirred for2 hours at room temperature. The mixture was partitioned between icewater and CH₂ Cl₂. The separated organic layer was washed with water,dried over MgSO₄, filtered and the filtrate evaporated. The oily residuewas purified by column chromatography over silica gel (eluent:toluene/2-propanol 94/6). The pure fractions were collected andevaporated. The residue was converted into the nitric acid salt (1:2) inCH₃ OH and crystallized from 2-propanone/diethyl ether, yielding 1.15 g(9%) (±)-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!ethyl!quinolilne dinitrate (intermediate 12;mp. 116.4° C.). In a similar manner, there were prepared: (±)-6-1H-1,2,4-triazol-1-yl 3-(trifluoromethyl)phenyl!propyl!quinoline(intermediate 13); (±)-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!2-methylpropyl!quinoline (intermediate 14);and (±)-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!pentyl!quinoline (intermediate 15).

EXAMPLE 5

Potassium t-butoxide (0.945 g) was added portionwise to a stirringmixture of (±)-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!methyl!quinoline (2.7 g) inN,N-dimethylformamide (80 ml) at 0° C. under N₂. The mixture was stirredfor 30 minutes at 0 ° C. and N-fluorosultam (2.43 g), disclosed in Helv.Chim. Acta 72 p. 1248 (1989), was added. Subsequently the mixture wasstirred at 0° C. for 1 hour and at room temperature for 1 hour. A few mlof water were added and the solvent was evaporated. The residue waspartitioned between water and ethylacetate. The separated organic layerwas washed with water, dried over MgSO₄, filtered and the filtrateevaporated. The oily residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 98/2). The pure fractions werecollected and evaporated. The residue was converted into the ethanedioicacid salt (1:1) in 2-propanone/diethyl ether, yielding (±)-6-fluoro(1H-1,2,4-triazol-1-yl) 3-trifluoromethyl)phenyl!methyl!quinolineethanedioate (intermediate 16; mp. 142.6° C.).

EXAMPLE 6

3-Chloroperoxybenzoic acid (49 g) was added portionwise to a solution ofintermediate 11 (50.3 g) in CH₂ Cl₂ (500 ml) and the mixture was stirredfor 1 hour at room temperature. The mixture was partitioned with a 10%NaHCO₃ solution. The separated organic layer was washed with a saturatedNaCl solution, dried over MgSO₄, filtered and the filtrate evaporated,yielding (-)-(R)-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl)-phenyl!methyl!quinoline, 1-oxide (intermediate 17;mp. 123.2° C.). In a similar manner, the following intermediates wereprepared.

    ______________________________________    1 #STR10##                                    Phys. Prop.    Intermediate               R.sup.2   R.sup.3    (mp. in ° C.)    ______________________________________    17         H         H          (-)-(R); 123.2    18         H         H          (+)-(S); 124.2    19         H         H          (±); 206.8    20         H         CH.sub.3   (±)    21         H         F          (±)    22         H         --CH.sub.2 CH.sub.3                                    (±)    23         H         --CH(CH.sub.3).sub.2                                    (±)    24         H         --(CH.sub.2).sub.3 CH.sub.3                                    (±)    25         8-CH.sub.3                         H          (±)    26         5-Cl      H          (±)    27         8-F       H          (±)    ______________________________________

EXAMPLE 7

a) Butyllithium (12.5 ml) was added dropwise at -78° C. to a solution of6-bromo-2-methoxyquinoline (4 g) in tetrahydrofuran (160 ml). Aftercomplete addition the mixture was stirred at -78° C. for 15 minutes. Asolution of 3-(trifluoromethyl)-benzaldehyde (3.51 g) in tetrahydrofuran(40 ml) was added dropwise and the mixture was stirred at -78° C. for 30minutes, then quenched with water (50 ml) and extracted withethylacetate. The organic layer was separated, washed with brine, driedover MgSO₄, filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH 97/3). The pure fractions were collected and the solvent wasevaporated, yielding 3.7 g (66%) of (±)-2-methoxy-α-3-(trifluoromethyl)phenyl!-6- quinoline methanol (intermediate 28).

b) A mixture of intermediate 28 (1 g) and HCl (25 ml; 3 N) was stirredand refluxed for 2 hours. The solution was basified with NaOH andextracted with CH₂ Cl₂. The organic layer was separated, washed withbrine, dried over MgSO₄, filtered and the solvent was evaporated,yielding 1.8 g of (±)-6- hydroxy3-(trifluoromethyl)phenyl!methyl!-2(1H-quinolinone (intermediate 29).

c) Thionylchloride (12.3 ml) was added dropwise at 0° C. to a solutionof intermediate 29 (12.3 g) in CH₂ Cl₂ (900 ml) and the mixture wasstirred for 1 hour. Thionylchloride (12.3 ml) was added again dropwiseat 0° C. and the mixture was stirred at room temperature for 1 hour.Thionylchloride (12.3 ml) was added again dropwise at 0° C. and themixture was stirred at room temperature for 1 hour. The mixture waspoured into ice and extracted. The organic layer was dried over MgSO₄,filtered off and the solvent was evaporated, yielding 13 g (100%) of(±)-6- chloro 3-(trifluoromethyl)phenyl!methyl!-2(1H)-quinolinone(intermediate 30).

B. Preparation of the Compounds of Formula (I) EXAMPLE 8

A 10% K₂ CO₃ solution (700 ml) and p-toluenesulfonyl chloride (36.8 g)were added to a solution of intermediate 17 (52.5 g) in CH₂ Cl₂ (700 ml)and the mixture was stirred at room temperature for 1 hour. The mixturewas washed with a saturated NaCl solution and the separated organiclayer was dried over MgSO₄, filtered and the filtrate evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂ Cl₂ /CH₃ OH 96.5/3.5). The pure fractions were collected andevaporated. The residue was crystallized from methyl ethylketon/diisopropyl ether, yielding 15.3 g (29%) (-)-(R)-6-1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!methyl!-2(1H)-quinolinone (compound 1; mp.192.8° C.; α!_(D) ²⁰ =-41.05° (c=99.87 mg/10 ml methanol)).

EXAMPLE 9

Alternatively, compound 1 was prepared by stirring a solution ofintermediate 17 (1.2 g) in acetic anhydride (10 ml) for 12 hours at 140°C. Excessive acetic anhydride was evaporated, the mixture was alkalizedwith a 10% K₂ CO₃ solution and extracted with CH₂ Cl₂. The separatedorganic layer was washed with a saturated NaCl solution, dried overMgSO₄, filtered and the filtrate evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5).The pure fractions were collected, evaporated and further purified bycolumn chromatography over Chiracel AD® (eluent: n-hexane/ethanol90/10). The pure fractions were collected and evaporated, yielding 0.235g (33.7%) of compound 1 (mp. 176.0° C.; α!_(D) ²⁰ =-45.62° (c=10.96mg/10 ml methanol)). The above reaction procedure was repeated a numberof times and a mixture of the resulting fractions was dissolved inmethyl ethyl keton (300 ml) and heated to complete dissolution. Themixture was filtered warm. The filtrate was rested for 18 hours,allowing the compound to recrystallize. The precipitate was filteredoff, washed with diisopropyl ether (100 ml) and dried, yielding 118 g(90.8%) of compound 1. This fraction was dried again, yielding 109.5 g(64.2%) of compound 1 (mp. 195° C.; α!_(D) ²⁰ =-42.12° (c=99.23 mg/10 mlmethanol)).

EXAMPLE 10

A mixture of intermediate 30 (0.846 g), 1,2,4-triazole (0.346 g) andpotassium carbonate (0.7 g) in CH₃ CN (30 ml) was stirred and refluxedfor 2 hours. The solvent was evaporated and the residue was taken up inwater and extracted with CH₂ Cl₂. The organic layer was dried MgSO₄,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH/NH₄ OH98/2/0.1) and the solvent of the desired fraction was evaporated,yielding 0.25 g (27%) of (±)-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!methyl!-2(1H)-quinolinone (compound 3).

The following table lists compounds that were prepared in a similar wayas in one of the hereinabove mentioned examples.

    ______________________________________    2 #STR11##    Comp. Exam-    No.   ple     R.sup.2 R.sup.3                                 Phys. Prop. (mp. in ° C.)    ______________________________________    1     8       H       H      (-)-(R); 192.8;  α!.sub.D.sup.20 =                                 -41.05°                                 (c = 99.87 mg/10 ml methanol)    1     9       H       H      (-)-(R); 195;  α!.sub.D.sup.20 =                                 -42.12°                                 (c = 99.23 mg/10 ml methanol)    2     8       H       H      (+)-(S); 193.9;  α!.sub.D.sup.20 =                                 40.72°                                 (c = 98.72 mg/10 ml methanol)    2     9       H       H      (+)-(S); 172.0;  α!.sub.D.sup.20 =                                 45.62°                                 (c = 10.96 mg/10 ml methanol)    3     9       H       H      (±); 192.2    3     10      H       H      (±)    4     8       H       CH.sub.3                                 (±); 255.6    5     8       H       F      (±); 231.6    6     8       H       CH.sub.2 CH.sub.3                                 (±); 170.3    7     8       H       CH(CH.sub.3).sub.2                                 (±); 205.0    8     8       H       (CH.sub.2).sub.3 CH.sub.3                                 (±); 217.1    9     8       8-CH.sub.3                          H      (±); 174.9    10    8       5-Cl    H      (±); 155.6    11    8       8-F     H      (±); 182.6    ______________________________________

EXAMPLE 11

A mixture of compound 3 (10 g) in N,N-dimethylformamide (100 ml) wasstirred at room temperature under N₂. Sodium hydride (0.51 g) was addedportionwise and the mixture was stirred for 15 minutes. The mixture wascooled, iodomethane was added dropwise and the reaction mixture wasstirred for 12 hours. The solvent was evaporated and the residue waspartitioned between CH₂ Cl₂ and water. The separated organic layer wasdried over MgSO₄, filtered and the filtrate evaporated. The oily residuewas purified by column chromatography over silica gel (eluent: CH₂ Cl₂/CH₃ OH/NH₄ OH 98/2/0.1). The pure fractions were collected and thesolvent was evaporated. The residue was crystallized from methyl ethylketon/diethyl ether, yielding 2.9 g(28%) (±)-1methyl-6-1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!methyl!-2(1H)-quinolinone (compound 12; mp.186.7° C.). In a similar manner, the following compounds were prepared:

    ______________________________________    3 #STR12##    Comp.    No.    R.sup.1  R.sup.2    Physical Properties (mp. in ° C.)    ______________________________________    12     H        CH.sub.3   (±); 186.7    13     F        CH.sub.3   (±); 148.1    14     CH.sub.3 CH.sub.3   (±); 159.1    15     CH.sub.2 CH.sub.3                    CH.sub.3   (±); 130.2    16     CH.sub.3 CH.sub.2 CH.sub.3                               (±); 125.8    17     CH.sub.3 (CH.sub.2).sub.2 CH.sub.3                               (±); 177.4    18     CH.sub.3 (CH.sub.2).sub.3 CH.sub.3                               (±); 143.5    19     CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2                               (±); 189.5    ______________________________________

EXAMPLE 12

A mixture of compound 3 (7.3 g) and NaOH (4.12 g) in water (20 ml) wasstirred at room temperature for 15 minutes. Hydroxylamine-O-sulfonicacid (6.3 g) was added portionwise and the mixture was stirred for 12hours. The precipitate was filtered off and crystallyzed from2-propanol, yielding 2.3 g (±)-(1-amino-6- 1H-1,2,4-triazol-1-yl-3-(trifluoromethyl)phenyl!methyl!-2(1H)-quinolinone (compound 20; mp.222.3° C.).

EXAMPLE 13

A mixture of compound 12 (7 g) and phosphorus pentasulfide (8.1 g) inpyridine (100 ml) was stirred and refluxed for 4 hours. The solvent wasevaporated, the residue was partitioned between water and CH₂ Cl₂. Theseparated organic layer was dried over MgSO₄, filtered and the filtrateevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH/NH₄ OH 99/1/0.1). The pure fractionswere collected and evaporated. The residue was crystallized fromdiisopropyl ether/methyl ethyl keton/2-propanone, yielding 1.4 g (20%)(±)-1-methyl-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl!phenyl!methyl!-2(1H)-quinolinethione (compound 21;mp. 143.7° C.). In a similar way, (±)-6- 1H-1,2,4-triazol-1-yl3-(trifluoromethyl!phenyl!methyl!-2-quinolinethiol (compound 22) wasprepared.

EXAMPLE 14

Compound 1 (3.7 g) was dissolved in ethanol (50 ml). HBr (gas) wasbubbled through the mixture for 2 minutes. The solvent was evaporatedand the residue was dissolved in CH₃ CN/C₂ H₅ OH 80/20. The solvent wasevaporated and the residue was triturated in methyl isobutyl keton. Theprecipitate was filtered off and dried. This fraction was recrystallizedfrom 2-propanone/2-propanol (35 ml/15 ml). The precipitate was filteredoff and dried. This fraction was recrystallized from ethanol in a closedchamber, saturated with 2-propanone. The liquid was decanted and thecrystals were dried, yielding 0.74 g (16.4%) of (R)-6-1H-1,2,4-triazol-1-yl3-(trifluoromethyl)phenyl!-methyl!-2(1H)-quinolinone monohydrobromide(1:1) (compound 23; mp. 220° C.).

C. Pharmacological examples Example 15: Inhibition of retinoic acid (RA)metabolism

MCF-7 human breast cancer cells were grown as stock cultures accordingto art-known protocols. One day before the experiment, RA is added tothe stock cultures to stimulate RA-metabolism. At the start of theexperiment, cell suspensions were incubated in a tissue culture mediumcontaining ³ H-RA as the substrate. Different concentrations of the testcompound (dissolved in 1% DMSO) were added to the incubation mixtures,and at the end of the incubation, the unmetabolized RA is separated fromits polar metabolites. The fraction containing the polar ³ H-labelledmetabolites was collected and counted in a scintillation counter. Foreach experiment, a control and a blank incubation were run in parallel.The IC₅₀ values listed in table 1 are the concentrations needed toreduce the amount of metabolites to 50% of the control.

Example 16: "Vaginal Keratinization Test on Ovariectomized Rats"

Ovariectomized rats were injected subcutaneously with a sesame oilsolution containing 100 μg of estradiol undecylate in a volume of 0.1 mlper 100 g body weight and control animals were injected with sesame oil.On day one, two and three, test animals were treated once daily with aper os dose of the test compound and control animals with the drugvehicle (PEG 200). One day after the last treatment, the animals weresacrificed and their vaginas were processed for histological evaluationaccording to the method described in J. Pharmacol. Exp. Ther. 261(2),773-779 (1992). A dose at which 50% of the tested rats show completesuppression of the estradiol undecylate induced keratinization effectsis defined as an active dose. The lowest active dose (LAD) for thecompounds of the present invention is listed in table 1.

The unexpected superiority of the compounds of the present inventionover the closest art-known compounds is demonstrated in table 2. In saidtable, the keratinization effect of the present compound number 3 iscompared to the structurally closest art-known compounds, the latterbeing disclosed in EP-0,371,564.

                  TABLE 1    ______________________________________                Keratinization    Compound Number                (LAD in mg/kg)                            RA Metabolism (IC.sub.50 in M)    ______________________________________    1           1.25         8.5 × 10.sup.-7    2           >40         3.85 × 10.sup.-6    3           2.5         8.51 × 10.sup.-7    4           5            5.1 × 10.sup.-7    5           5             >1 × 10.sup.-5    6           10          1.82 × 10.sup.-8    7           >20          2.7 × 10.sup.-7    9           10          7.06 × 10.sup.-7    10          10          7.64 × 10.sup.-7    11          10          1.54 × 10.sup.-7    12          2.5         8.59 × 10.sup.-6    13          --          1.02 × 10.sup.-8    14          5           3.25 × 10.sup.-9    15          2.5           >1 × 10.sup.-6    16          10            >1 × 10.sup.-6    17          >10         1.07 × 10.sup.-8    18          >10           >1 × 10.sup.-7    19          >10           >1 × 10.sup.-7    20          5           1.47 × 10.sup.-6    21          5           4.37 × 10.sup.-6    ______________________________________

                                      TABLE 2    __________________________________________________________________________    EP-0,371,564                present invention    Compound             LAD (mg/kg)                                Compound             LAD (mg/kg)    __________________________________________________________________________     ##STR13##    4                    40                                6 #STR14##           2.5    Comp. No. 11-a              Comp. No. 3    5 #STR15##           10    Comp. No. 66-a    __________________________________________________________________________

D. Composition examples

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic or topical administration to animal and humansubjects in accordance with the present invention.

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I) or a pharmaceutically acceptable acid additionsalt thereof.

Example 17: oral solution

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxy-benzoatewere dissolved in 4 l of boiling purified water. In 3 l of this solutionwere dissolved first 10 g of 2,3-dihydroxybutanedioic acid andthereafter 20 g of A.I. 1 and/or 0.2 g of A.I. 2. The latter solutionwas combined with the remaining part of the former solution and 12 l1,2,3-propane-triol and 3 l of sorbitol 70% solution were added thereto.40 g of sodium saccharin were dissolved in 0.5 l of water and 2 ml ofraspberry and 2 ml of gooseberry essence were added. The latter solutionwas combined with the former, water was added q.s. to a volume of 20 lproviding an oral solution comprising 5 mg of A.I. 1 and/or 0.05 mg ofA.I. 2 per teaspoonful (5 ml). The resulting solution was filled insuitable containers.

Example 18: oral drops

500 g of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acid and1.5 l of the polyethylene glycol at 60˜80° C. After cooling to 30˜40° C.there were added 35 l of polyethylene glycol and the mixture was stirredwell. Then there was added a solution of 1750 g of sodium saccharin in2.5 l of purified water and while stirring there were added 2.5 l ofcocoa flavor and polyethylene glycol q.s. to a volume of 50 l, providingan oral drop solution comprising 10 mg/ml of A.I. The resulting solutionwas filled into suitable containers.

Example 19: capsules

20 g of A.I. 1 and/or 0.2 g of A.I. 2, 6 g sodium lauryl sulfate, 56 gstarch, 56 g lactose, 0.8 g colloidal silicon dioxide, and 1.2 gmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, each comprising 20 mg of A.I. 1 and/or 0.2 mg of A.I. 2.

Example 20: injectable solution

0.5 mg A.I. 1 and/or 0.05 mg A.I. 2, 50 mg glucose anhydrous and 0.332ml concentrated hydrochloric acid were mixed with 0.8 ml water forinjections. Sodium hydroxide was added until pH=3.2±0.1 and water wasadded to 1 ml. The solution was sterilized and filled in sterilecontainers.

Example 21: film-coated tablets Preparation of tablet core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90®) in about 200 mlof water. The wet powder mixture was sieved, dried and sieved again.Then there was added 100 g microcrystalline cellulose (Avicel®) and 15 ghydrogenated vegetable oil (Sterotex®). The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each comprising 10 mg ofthe active ingredient.

Coating

To a solution of 10 g methyl cellulose (Methocel 60 HG®) in 75 ml ofdenaturated ethanol there was added a solution of 5 g of ethyl cellulose(Ethocel 22 cps®) in 150 ml of dichloromethane. Then there were added 75ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g ofpolyethylene glycol was molten and dissolved in 75 ml ofdichloromethane. The latter solution was added to the former and thenthere were added 2.5 g of magnesium octadecanoate, 5 g ofpolyvinylpyrrolidone and 30 ml of concentrated color suspension(Opaspray K-1-2109®) and the whole was homogenated. The tablet coreswere coated with the thus obtained mixture in a coating apparatus.

Example 22: 2% cream

75 mg stearyl alcohol, 2 mg cetyl alcohol, 20 mg sorbitan monostearateand 10 mg isopropyl myristate are introduced into a doublewall jacketedvessel and heated until the mixture has completely molten. This mixtureis added to a separately prepared mixture of purified water, 200 mgpropylene glycol and 15 mg polysorbate 60 having a temperature of 70 to75° C. while using a homogenizer for liquids. The resulting emulsion isallowed to cool to below 25° C. while continuously mixing. A solution of20 mg A.I., 1 mg polysorbate 80 and purified water and a solution of 2mg sodium sulfite anhydrous in purified water are next added to theemulsion while continuously mixing. The cream, 1 g of the A.I. ishomogenized and filled into suitable tubes.

Example 23: 2% topical gel

To a solution of 200 mg hydroxypropyl b-cyclodextrine in purified wateris added 20 mg of A.I. while stirring. Hydrochloric acid is added untilcomplete dissolution and then sodium hydroxide is added until pH 6.0.This solution is added to a dispersion of 10 mg carrageenan PJ in 50 mgpropylene glycol while mixing. While mixing slowly, the mixture isheated to 50° C. and allowed to cool to about 35° C. whereupon 50 mgethyl alcohol 95% (v/v) is added. The rest of the purified water q.s. ad1 g is added and the mixture is mixed to homogenous.

Example 24: 2% topical cream

To a solution of 200 mg hydroxypropyl b-cyclodextrine in purified wateris added 20 mg of A.I. while stirring. Hydrochloric acid is added untilcomplete dissolution and next sodium hydroxide is added until pH 6.0.While stirring, 50 mg glycerol and 35 mg polysorbate 60 are added andthe mixture is heated to 70° C. The resulting mixture is added to amixture of 100 mg mineral oil, 20 mg stearyl alcohol, 20 mg cetylalcohol, 20 mg glycerol monostearate and 15 mg sorbate 60 having atemperature of 70° C. while mixing slowly. After cooling down to below250° C., the rest of the purified water q.s. ad 1 g is added and themixture is mixed to homogenous.

Example 25: 2% liposome formulation

A mixture of 2 g A.I. microfine, 20 g phosphatidyl choline, 5 gcholesterol and 10 g ethyl alcohol is stirred and heated at 55-60° C.until complete dissolution and is added to a solution of 0.2 g methylparaben, 0.02 g propyl paraben, 0.15 g disodium edetate and 0.3 g sodiumchloride in purified water while homogenizing. 0.15 gHydroxypropyl-methylcellulose in purified water ad 100 g is added andthe mixing is continued until swelling is complete.

Example 26: 2% liposome formulation

A mixture of 10 g phosphatidyl choline and 1 g cholesterol in 7.5 gethyl alcohol is stirred and heated at 40° C. until completedissolution. 2 g A.I. microfine is dissolved in purified water by mixingwhile heating at 40° C. The alcoholic solution is added slowly to theaqueous solution while homogenizing during 10 minutes. 1.5 gHydroxypropyl-methylcellulose in purified water is added while mixinguntil swelling is complete. The resulting solution is adjusted to pH 5.0with sodium hydroxide 1 N and diluted with the rest of the purifiedwater ad 100 g.

We claim:
 1. A compound of formula ##STR16## a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein:R¹ is hydrogen, amino or C₁₋₄ alkyl.; R² is hydrogen, halo or C₁₋₄ alkyl; R³ is hydrogen, halo or C₁₋₄ alkyl; Y is O or S; and --X¹ ═X² --is a bivalent radical having the formula--N═CH-- (a-1) or --CH═N-- (a-2).
 2. A compound according to claim 1 wherein --X¹═X² --is a bivalent radical of formula (a-1).
 3. A compound according to claim 2, wherein Y is O.
 4. A compound according to claim 3, wherein R¹ is hydrogen or methyl, R² is hydrogen and R³ is hydrogen, methyl or ethyl.
 5. A compound according to claim 1, wherein the compound is (-)-(R)-6- 1H-1,2,4-triazol-1-yl 3-(trifluoromethyl!phenyl!methyl!-2(1H)-quinolinone; or the pharmaceutically acceptable acid addition salts thereof.
 6. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in claim
 1. 7. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in claim
 2. 8. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in claim
 3. 9. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in claim
 4. 10. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in claim
 5. 11. A method of treating psoriasis in patients in need of the same which comprises the topical or systemic administration to said patients of a therapeutically effective amount of a compound as claimed in claim
 1. 12. A method of treating psoriasis in patients in need of the same which comprises the topical or systemic administration to said patients of a therapeutically effective amount of a compound as claimed in claim
 2. 13. A method of treating psoriasis in patients in need of the same which comprises the topical or systemic administration to said patients of a therapeutically effective amount of a compound as claimed in claim
 3. 14. A method of treating psoriasis in patients in need of the same which comprises the topical or systemic administration to said patients of a therapeutically effective amount of a compound as claimed in claim
 4. 15. A method of treating psoriasis in patients in need of the same which comprises the topical or systemic administration to said patients of a therapeutically effective amount of a compound as claimed in claim
 5. 16. A process of preparing a compound as claimed in claim 1, characterized in that: a) a nitrone of formula ##STR17## wherein R², R³ and --X¹═X²⁻ are defined as in claim 1, is reacted with p-toluenesulfonylchloride thus obtaining a compound of formula ##STR18## 